Epidermolysis Bullosa Acquisita

Diagnosis

Indications for Testing

  • Presence of chronic blistering, erosive and/or crusting skin disease
  • More common diseases ruled out

Laboratory Testing

  • Initial serum testing – test for pemphigus, pemphigoid, and endomysial antibodies, or epithelial skin antibodies
    • Broad screening recommended unless a specific immunobullous skin disease type is suspected
    • Serologic diagnosis – positive in 90% of cases
  • Pemphigoid panel – IgG basement membrane zone (BMZ) antibodies positive titer >1:10 with dermal pattern is diagnostic for epidermolysis bullosa acquisita (EBA)
    • Collagen type VII antibody IgG by ELISA

Histology

  • Immunohistology
    • Perilesional skin biopsy for direct immunofluorescence (DIF) – gold standard for diagnosis
      • Linear BMZ deposition of IgG and/or third component of complement (C3) along BMZ of perilesional tissue
    • Dermal pattern localization of serum IgG BMZ antibodies on human split skin substrate by indirect immunofluorescence

      • Characteristically found in EBA
      • Also found in
        • Subset of bullous systemic lupus erythematosus
        • Two subsets of pemphigoid
          • Anti-laminin 332 pemphigoid
          • Anti-laminin γ1 pemphigoid
      • Collagen VII IgG antibodies not increased
        • Up to one third of laminin 332 antibody pemphigoid cases with dermal pattern BMZ antibody staining have underlying malignancy or will be diagnosed with malignancy in a few months
        • Further clinical evaluation should be pursued as indicated
      • Collagen VII antibodies increased
        • Unknown whether patients also may have laminin 332 antibodies
        • The association with malignancy and dermal pattern BMZ antibody staining should be considered

Differential Diagnosis

Monitoring

  • Collagen type VII IgG antibody and epithelial skin antibody OR

  • Collagen type VII IgG antibody and IgG BMZ antibodies

Clinical Background

Epidermolysis bullosa acquisita (EBA) is a rare, chronic autoimmune blistering disease.

Epidemiology

  • Incidence – 25/10,000
  • Age – all ages; peak onset in 40s (this acquired autoimmune form typically develops in adulthood, in contrast to hereditary types of epidermolysis bullosa that are present in early infancy)
  • Sex – M:F, equal

Pathophysiology

  • Subepidermal blister formation characterized by autoantibodies to structural components of skin and adjacent mucous membranes (specifically collagen VII)
  • Collagen VII – component of anchoring fibrils within epithelial basement membrane zone (BMZ) (skin and mucous membranes)
    • Patients with EBA characteristically develop IgG antibodies to collagen VII
    • Major epitopes for EBA antibody reactivity reside in non-collagenous amino-terminal domain (NC1)
    • Minor epitopes reside in non-collagenous carboxy-terminal domain (NC2) of the three identical alpha chains that comprise collagen VII

Clinical Presentation

  • Blistering lesions of skin on areas of trauma and/or oral mucosa with an acral distribution that heals with atrophy and skin pigmentation changes
    • Tense blisters with serous or hemorrhagic fluid
    • Milia (inclusion cysts) may form in and around blisters
    • Primary location – areas subjected to repetitive minor trauma (extensor surfaces of elbows, knees, hands, feet)
  • Alopecia
  • Mucosal disease
  • Nail dystrophy
  • Complications – infections, pain

Treatment

  • Challenging to put into remission
  • Variety of agents currently in use, including colchicine, cyclosporine, prednisone, and dapsone

Indications for Laboratory Testing

  • Tests generally appear in the order most useful for common clinical situations
  • Click on number for test-specific information in the ARUP Laboratory Test Directory
Test Name and Number Recommended Use Limitations Follow Up
Cutaneous Direct Immunofluorescence, Biopsy 0092572
Method: Direct Immunofluorescence
(Direct Fluorescent Antibody Stain)

Use to determine the presence and characteristic staining pattern of immunoglobulins (IgG, IgM, IgA), third component of complement (C3) and fibrinogen in skin or mucous membrane biopsy specimens (biopsy site is critical; see below) from patients suspected of having epidermolysis bullosa acquisita (EBA); perform this test with serum pemphigoid and pemphigus panel tests

For skin involvement, biopsy perilesional skin

For mucous membrane involvement, biopsy nonlesional mucosa

See Immunobullous Skin Diseases Testing algorithm

Clinical correlation necessary because the incidence of false-positives, although rare, increases with age

Because of clinical overlap among immunobullous diseases and similar names, pemphigoid testing may be confused with pemphigus testing and inadvertently misordered

Initial concurrent and repeat serum testing with pemphigoid panel is the most sensitive for diagnosis, for determining antibody profiles, and for following disease activity

Patients with indeterminate results should have repeat DIF biopsy

Patients with changing clinical features should have repeat DIF biopsy because antibody profiles may change over time

See Immunobullous Skin Diseases Testing algorithm

Pemphigoid Antibody Panel - Epithelial Basement Membrane Zone Antibodies, IgG and IgA, BP180 and BP230 Antibodies, IgG 0092001
Method: Enzyme-Linked Immunosorbent Assay/Indirect Fluorescent Antibody

Panel includes epithelial basement membrane zone (BMZ) IgG & IgA antibodies by indirect immunofluorescence (IFA) on split human skin and monkey esophagus substrates, BP180 & BP230 IgG antibodies by ELISAs

Use to diagnose most types of pemphigoid, EBA, linear IgA disease (including linear IgA bullous dermatosis and chronic bullous disease of childhood), mixed immunobullous disease

Use along with pemphigus panel and endomysial antibody IgA testing to initially diagnose and discriminate among the immunobullous skin diseases in patients suspected or known to have any type of immunobullous disease

Use to monitor disease activity and therapeutic response

Concurrent perilesional skin biopsy for DIF is important for diagnosis because of increased sensitivity (85-100% of EBA cases are positive)

See Immunobullous Skin Diseases Testing algorithm

Clinical correlation necessary because the incidence of false-positives, although rare, increases with age

Because of clinical overlap among immunobullous diseases and similar names, pemphigoid testing may be confused with pemphigus testing and inadvertently misordered

Use pemphigoid panel or epithelial BMZ IgG antibody test to monitor EBA disease activity and response to therapy

Repeat pemphigoid panel or epithelial BMZ IgG antibody test for indeterminate results and/or continuing clinical consideration of EBA

See Immunobullous Skin Diseases Testing algorithm

Collagen Type VII Antibody IgG by ELISA  2010905
Method: Enzyme-Linked Immunosorbent Assay

Aid in the diagnosis of EBA and monitoring of disease activity

Use along with pemphigoid panel test or use epithelial skin antibody testing to initially diagnose and discriminate among the immunobullous skin diseases in patients suspected or known to have any type of immunobullous disease

See Immunobullous Skin Diseases Testing algorithm

May not be positive in all patients with EBA, including those with antibodies to other epitopes in collagen VII than those expressed in ELISA

May also be positive in patients with bullous lupus erythematosus, inflammatory bowel disease, and Crohn disease

Patients with EBA may develop antibodies to other basement membrane components

Use with pemphigoid panel or epithelial IgG BMZ antibodies to follow disease activity in EBA

Repeat test for indeterminate results and/or continuing clinical consideration of EBA

See Immunobullous Skin Diseases Testing algorithm

Pemphigus Antibody Panel - Epithelial Cell Surface Antibodies and Desmoglein 1 and Desmoglein 3 Antibodies, IgG 0090650
Method: Enzyme-Linked Immunosorbent Assay/Indirect Fluorescent Antibody

Panel includes epithelial cell surface IgG antibodies by IFA on intact human skin and monkey esophagus substrates, desmoglein 1 and desmoglein 3 IgG antibodies by ELISAs

Use to diagnose most major types of pemphigus and to monitor disease activity and therapeutic response

Use along with pemphigoid panel and endomysial IgA antibody tests to initially diagnose and distinguish various immunobullous disorders in patients suspected or known to have any type of immunobullous disease

See Immunobullous Skin Diseases Testing algorithm

Clinical correlation is necessary because cell surface antibodies by IFA, usually in low titers, may be found in normal individuals (possible blood group reactivity) or in patients with fungal infections, burns, drug reactions and other dermatoses, including other immunobullous diseases

Because of clinical overlap among immunobullous diseases and similar names, pemphigoid testing may be confused with pemphigus testing and inadvertently misordered

Testing for IgG pemphigus antibody types (most common) also may be confused with IgA pemphigus testing (rare disorder)

 
Tissue Transglutaminase (tTG) Antibody, IgA with Reflex to Endomysial Antibody, IgA by IFA 0050734
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody
Use along with pemphigoid and pemphigus panel tests, or use with epithelial skin antibody testing to initially diagnose and discriminate among the immunobullous skin diseases in patients suspected or known to have any type of immunobullous disease

May be negative if patient is following a gluten-free diet

False-positive IgA antibody levels may occur in other inflammatory bowel diseases

 
Epithelial Skin Antibody 0090299
Method: Indirect Immunofluorescence
(Indirect Fluorescent Antibody)

Panel includes epithelial BMZ IgG and IgA antibodies by IFA and IgG and IgA cell surface antibodies by IFA on split human skin, intact human skin and monkey esophagus substrates

Use as alternate to pemphigoid and pemphigus panel tests to initially diagnose and discriminate among clinically similar immune-mediated skin diseases such as EBA, pemphigus, linear IgA disease, pemphigoid, and dermatitis herpetiformis in patients suspected of having or known to have any type of subepidermal immunobullous disease

Although helpful in screening for immunobullous disease, test is not as sensitive as combination of pemphigus and pemphigoid panels

Use epithelial skin antibody test or both pemphigoid and pemphigus panels to follow patients with changing clinical features because antibody profiles may change over time

See Immunobullous Skin Diseases Testing algorithm

Epithelial Basement Membrane Zone Antibody IgG 0092056
Method: Indirect Immunofluorescence
(Indirect Fluorescent Antibody)

This test comprises components included in pemphigoid panel, epithelial skin antibody, and pemphigoid gestationis tests

Use to establish or confirm diagnosis of EBA or pemphigoid in patients suspected of having or known to have any type of disorder with IgG BMZ antibodies

Use to distinguish EBA from pemphigoid

Clinical correlation necessary because the incidence of false positives, although rare, increases with age

This test does NOT detect IgA BMZ antibodies; linear IgA disease and dermatitis herpetiformis will NOT be detected

Use epithelial BMZ IgG antibodies test to follow patients with EBA

Repeat epithelial basement membrane zone IgG antibodies test for indeterminate results and/or continuing clinical consideration of EBA

See Immunobullous Skin Diseases Testing algorithm